Devices and methods and agent-assisted medical procedures

ABSTRACT

Various embodiments of bulking or cushioning agents or material and related medical devices and methods are disclosed. For example, a method of performing a medical procedure in a tract of a body may include injecting a material in a liquid phase proximate a target site between a first tissue layer and a second tissue layer, allowing the material to transition from the liquid phase to the gel phase in response to a raise in temperature of the material to approximately at or above the predetermined temperature, and performing a surgical procedure on the target site. The material may have the liquid phase at temperatures below a predetermined temperature and a gel phase at temperatures approximately at or above the predetermined temperature.

This is a continuation of application Ser. No. 13/609,822, filed Sep.11, 2012, now U.S. Pat. No. 8,864,738, which is a continuation ofapplication Ser. No. 13/024,642, filed Feb. 10, 2011, now U.S. Pat. No.8,282,621, which is a continuation of U.S. application Ser. No.11/231,293, filed Sep. 21, 2005, now U.S. Pat. No. 7,909,809, whichclaims the benefit of priority under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 60/612,797, filed on Sep. 27, 2004, all ofwhich are incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

This invention relates to medical devices and related methods thereof.In a particular embodiment, this invention relates to devices andrelated methods for performing agent-assisted endoscopic procedures in,for example, a gastrointestinal (GI) tract of a patient.

DESCRIPTION OF RELATED ART

An endoscope is a medical device that enables viewing of the interior ofa body cavity or hollow organ without employing invasive surgicalprocedures. The endoscope includes an elongated flexible tube having asuitable imaging device at its distal end portion. This tube may beinserted through a naturally occurring opening, such as the esophagus orrectum, or through a small incision surgically made in the body.Suitable surgical instruments may be passed through the tube to performvarious medical procedures, such as for example, tissue sampling orremoval of diseased tissue or polyps.

Endoscopic procedures are commonly used for diagnosis and/or treatmentof the GI tract. For example, an endoscopic procedure may be performedto take tissue samples from the GI tract for pathological evaluationand/or therapeutic purposes. For example, with advances in the imagingtechnology, endoscopic procedures may be used to accurately detect andremove pre-cancerous mucosal tissue or tumors from various locations inthe GI tract.

Currently, interventional endoscopists perform fluid-assistedpolypectomy, endoscopic mucosal resection (EMR), and endoscopicsubmucosal dissection (ESD) procedures to remove pre-cancerous mucosaltissue from the GI tract. Such a fluid-assisted procedure may involveinjecting a saline fluid cushion between the mucosal and submucosaltissue layers so as to raise or separate the target mucosal tissue layerfrom the submucosal tissue layer in order to safely perform theprocedure (e.g., by preventing or reducing risks of perforating the GItract).

Currently available fluids for this purpose, however, dissipate quicklyand therefore cannot provide a long lasting cushioning effect for theentire duration of the procedure. For example, sterile saline, which isthe most commonly used fluid, typically provides a suitable cushion foronly about 3 to 5 minutes. When the fluid is dissipated, the endoscopistmust re-inject the fluid to assure the target tissue layer remainsraised or bulked. The more times the tissue is pierced with an injectionneedle to inject the fluid, the more holes that are created for thefluid to leak out.

Although there are fluids that last longer than the sterile saline, suchas hydroxypropyl methyl cellulose and hyaluronic acid, these fluids aremerely more viscous so as not to flow as quickly as the less viscousfluids do. Nevertheless, these fluids usually provide a suitable cushionfor only about 30 minutes, and are much more difficult to inject throughthe injection device because they require higher injection pressure dueto their higher viscosities.

SUMMARY OF THE INVENTION

Therefore, various embodiments of the invention relate to bulking orcushioning agents or other like materials for use in medical procedures,such as a fluid- or agent-assisted endoscopic procedure, and relatedmethods of using those agents or materials in such a procedure.According to embodiments, the agents or material may be easy to inject,stable for the duration of the entire procedure (e.g., typically lastingfrom about 30 minutes to about 12 hours), and/or easy to remove when theagent or material is no longer needed. While an embodiment of thepresent invention will be described in connection with an endoscopicprocedure (i.e., tissue resection) in the GI tract, embodiments of theinvention may be used in other suitable endoscopic procedures or appliedto different parts of a body, other than the GI tract. Embodiments ofthe invention may also be applied to numerous procedures other than theendoscopic procedures, such as urologic procedures, plastic surgeries,or open invasive surgeries.

To attain the advantages and in accordance with the purpose of theinvention, as embodied and broadly described herein, one aspect of theinvention may provide a method of performing a medical procedure in atract of a body. The method may include injecting a material in a liquidphase proximate a target site between a first tissue layer and a secondtissue layer, where the material may have the liquid phase attemperatures below a predetermined temperature and a gel phase attemperatures approximately at or above the predetermined temperature.The method may further include allowing the material to transition fromthe liquid phase to the gel phase in response to a raise in temperatureof the material to approximately at or above the predeterminedtemperature, and performing a surgical procedure on the target site.

According to another aspect of the invention, the method may includeremoving the material from the target site. Removing the material mayinclude injecting a cold fluid into the target site in contact with thematerial, allowing the material to transition from the gel phase to theliquid phase. In still another aspect, performing a surgical proceduremay include removing tissue from the target site. In still yet anotheraspect of the invention, the method may further may include positioningan endoscope in the vicinity of a target site.

In various aspects of the invention, the predetermined temperature maybe a temperature of the body.

In another aspect, the material may includepolyoxyethylene-polyoxypropylene block copolymers. The molecular weightsof the block copolymers may range from approximately 5,000 toapproximately 25,000.

According to still another aspect of the invention, the material mayremain in the gel phase for at least approximately 30 minutes.

In an aspect, the material may raise the first tissue layer. In anotheraspect of the invention, the first tissue layer may be a mucosal tissuelayer, and the second tissue layer may be a submucosal tissue layer. Instill another aspect, the tract may be a gastrointestinal tract.

In various aspects, the material may comprise poly(n-isopropylacrylamide). Alternatively or additionally, the material may comprisethermally sensitive inorganic-organic hybrid gels or block copolymer.The thermally sensitive block copolymer may comprise poly(N-isopropylacrylamide-b-dl-lactide). The material may comprise polyvinyl alcohol.The material may be configured to be responsive to a change in its pHlevel.

An aspect of the invention may provide a method of performing a medicalprocedure in a tract of a body. The method may include injecting amaterial in a liquid phase proximate a target site between a firsttissue layer and a second tissue layer, the material having the liquidphase at pH levels below a predetermined pH level and having a gel phaseat pH levels approximately at or above the predetermined pH level. Themethod may further include allowing the material to transition from theliquid phase to the gel phase in response to a raise in pH of thematerial to approximately at or above the predetermined pH level, andperforming a surgical procedure on the target site.

Another aspect of the invention may provide a system for performing amedical procedure. The system may include an elongated member having asharp distal end configured to pierce through tissue and a cushioningmaterial contained in the elongated member and configured to flow out ofthe distal end of the elongated member. The material may have a liquidphase at temperatures below a predetermined temperature and have a gelphase at temperatures approximately at or above the predeterminedtemperature.

In still another aspect of the invention, the elongated member maycomprise a syringe needle. Alternatively or additionally, the elongatedmember may comprise an elongated lumen connecting a proximal handle andthe distal end. The cushioning material may be contained in the lumen.In yet still another aspect, the system may include an end effector forperforming a surgical procedure. In an aspect, the system may alsoinclude a lumen extending from a fluid port in a proximal handle to thedistal end.

Additional objects and advantages of the invention will be set forth inpart in the description which follows, and in part will be obvious fromthe description, or may be learned by practice of the invention. Theobjects and advantages of the invention will be realized and attained bymeans of the elements and combinations particularly pointed out in theappended claims.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate various exemplary embodiments ofthe invention and together with the description, serve to explain theprinciples of the invention.

In the drawings:

FIG. 1 is a schematic cross-sectional view of mucosal and submucosaltissue layers in a GI tract, showing diseased tissue in the mucosaltissue layer;

FIG. 2 is a schematic cross-sectional view of mucosal and submucosaltissue layers in the GI tract, illustrating an exemplary method step ofinjecting a bulking or cushioning material between the mucosal andsubmucosal tissue layers;

FIG. 3 is a schematic cross-sectional view of mucosal and submucosaltissue layers in the GI tract, showing the raised mucosal tissue layerresulting from the injection of the cushioning material;

FIG. 4 is a schematic cross-sectional view of mucosal and submucosaltissue layers in the GI tract, illustrating an exemplary method step ofremoving diseased tissue from the mucosal tissue layer;

FIG. 5 is a schematic cross-sectional view of mucosal and submucosaltissue layers in the GI tract, illustrating an exemplary method step ofremoving the bulking or cushioning material from the mucosal andsubmucosal tissue layers; and

FIG. 6 is a schematic cross-sectional view of mucosal and submucosaltissue layers in the GI tract, showing the condition of the mucosal andsubmucosal tissue layers after the endoscopic procedures.

DESCRIPTION OF THE EMBODIMENTS

Reference will now be made in detail to the exemplary embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. Wherever possible, the same reference numbers will be usedthroughout the drawings to refer to the same or like parts.

In performing a fluid or other agent assisted, interventional endoscopicprocedure in the GI tract, such as, for example, polypectomy, endoscopicmucosal resection (EMR), or endoscopic submucosal dissection (ESD),various exemplary embodiments of the invention may utilize a bulking orcushioning material that has characteristics of phase transformation ortransition from a low viscosity state (e.g., liquid phase) into a highviscosity state (e.g., gel phase) in response to a predeterminedtemperature (e.g., body temperature).

Such a material may be referred to as a lower critical solutiontemperature (LCST) material, where the LCST refers to the temperature atwhich the transition from a liquid phase to a gel phase occurs. When theLCST material is injected into a body, the temperature of the LCSTmaterial may increase due to heat transfer from the body or other methodof increasing the temperature of the surrounding environment. Once thetemperature of the LCST material reaches the level of the LCST, thetransition from the liquid phase to the gel phase may take place. TheLCST may be a specific temperature or a range of temperatures. The LCSTmay be a material property and can be controlled by carefully selectingor preparing the LCST material to be used.

For example, the LCST material may be configured or prepared to remainin a liquid phase, with a low viscosity, at any temperature below thebody temperature (i.e., ˜37° C.), and to transform to a gel phase at orabove the body temperature. Since the viscosity of the material in theliquid phase is low, the material can be injected into a body in asimilar manner as is currently used for saline. Once the material isplaced at a target site within a body, the material may becomegelatinized or solidified due to the effect of the body temperature. Inthis phase, the material may remain in the injected location for theentire duration of the endoscopic procedure until it is removed fromthat location, thereby providing a more stable bulking or cushioningeffect and eliminating the need for additional injection of material.

The LCST material may also be readily removed from the target site afteran endoscopic procedure is completed. For example, due to the samecharacteristics of temperature-sensitive transition, cold water orsaline may be injected into the target site so as to allow thetemperature of the LCST material to decrease. The decrease in thetemperature of the LCST material will change its phase from the gelphase back to the liquid phase, enabling it to be flushed away from thetarget site together with the injected cold water or saline.

Suitable LCST materials for use, according to various exemplaryembodiments of the invention, may comprisepolyoxyethylene-polyoxypropylene (PEO-PPO) block copolymers. Twoacceptable compounds may include Pluronic acid F127 and F108, which arePEO-PPO block copolymers with molecular weights of 12,600 and 14,600,respectively. Each of these compounds may be available from BASF ofMount Olive, N.J. Other PEO-PPO block copolymers that have similarcharacteristics of LCST materials and are biocompatible andbiodegradable, may also be used. In general, PEO-PPO block copolymershaving molecular weights ranging, for example, between 5,000 and 25,000,and more particularly between 7,000 and 15,000, may be used.

In an exemplary embodiment, Pluronic acid F108 at 20-28% concentrationin phosphate buffered saline (PBS) may be used as LCST material.Preferably, Pluronic acid F108 at 22.5% concentration in PBS may beused. A preparation of 22% Pluronic acid F108 in PBS has an LCST ofapproximately 37° C. In another exemplary embodiment, Pluronic acid F127at 20-35% concentration in PBS may be used. By way of example, 20%Pluronic acid F127 in PBS has an LCST of approximately 37° C.

Other LCST materials appropriate for use, according to another exemplaryembodiment of the invention, may include poly(N-isopropyl acrylamide)(PNIPAA). For example, temperature-responsive copolymer (or ternarycopolymer) gels of N-isopropyl acrylamide (IPAAm) may be synthesizedwith one or more comonomers (e.g., hydrophobic alkyl methacrylate (RMA),hydrophilic acrylamide (AAm), N,N′-dimethylacrylamide (DMAAm), and/orN-acryloylpyrrolidine (APy)) to control transition temperature andthermo-sensitivity of the gel.

For example, introduction of hydrophobic RMA may lower the LCST of poly(IPAAm) gel in PBS, and the change in material property (e.g., materialrigidity, equilibrium swelling ratio, etc.) in response to temperaturemay become smaller with an increase of RMA content. In case the LCSTmaterial carries a therapeutic agent, RMA may be useful in regulatingthe release of the agent (e.g., due to RMA's hydrophobic interaction ofalkyl chains) by controlling the temperature at which the agent may bereleased (e.g., on-off regulation) from the surface of the LCSTmaterial.

Introduction of AAm may increase the LCST of poly (IPAAm) gel, and thethermo-sensitivity of the gel may become smaller with an increase of AAmcontent. Hydrophilic AAm may prevent the formation of a dense skin layer(e.g., at the outer surface of the LCST material) at a highertemperature.

Introduction of DMAAm or APy may increase the LCST. DMAAm or APy mayalso increase the thermo-sensitivity of the LCST material, such that thematerial may effectively respond even in a small temperature change.This may be useful in enabling ‘on-off’ drug release responsive tosmaller temperature changes in the body temperature range.

In still another exemplary embodiment, thermally sensitiveinorganic-organic (hybrid) gels may be used. For example, the gels maybe prepared by hybridizing porous silica and poly(N-isopropylacrylamide)gels (PNIPAAm gel). The internal pores of the silica may be filled withPNIPAAm gel to form a temperature-sensitive filler (e.g., drugreservoir). Alternatively or additionally, silica or other inorganicfiller may be surface grafted with a temperature-sensitive polymer.

A thermally sensitive block copolymer, such as, for example,poly(N-isopropyl acrylamide-b-dl-lactide) (PIPAAm-PLA), may also beused. The polymer may be synthesized by ring-opening polymerization ofdl-lactide, initiated from hydroxy-terminated poly(N-isopropylacrylamide) (PIPAAm). A PIPAAm, bearing a single terminalhydroxyl group, may be prepared by telomerization using2-hydroxyethanethiol as a chain-transfer agent. Successful preparationof PIPAAm and the PIPAAm-PLA block copolymer may be verified by gelpermeation chromatography (GPC) and ¹H-NMR spectroscopy. Polymericmicelles may be prepared from block copolymers using a dialysis method.Their solutions may show reversible changes in optical properties, suchas transparency below a LCST and opaque above the LCST. Dynamic lightscattering measurements were used to observe the formation of micellarstructures approximately 40 nm in diameter, which do not change between20° C. and 30° C. Above the LCST, polymer micelles aggregated, aphenomenon found to be reversible since the aggregates dissociated againby cooling below the LCST.

Other LCST materials appropriate for use, according to various exemplaryembodiments of the invention, may include, but are not limited to,degradable oligomers of Poloxamer 407 having either carbonate or urealinkages in the backbone structure, and Poloxamer 407.

Besides the LCST materials, according to various other exemplaryembodiments of the invention, the cushioning or bulking materials may beconfigured to be responsive to other stimuli, such as pH or light. Forexample, the cushioning or bulking material may be injected in aflowable low-viscosity phase into a body where the material may beexposed to a predetermined pH level (e.g., 7.4 in the body). Thelow-viscosity material may then be mixed with a body fluid to change itspH level. The change in the pH level may change its phase from theflowable low-viscosity material to a more stable semi-rigid gel phase.

In various exemplary embodiments, the cushioning or bulking materialsmay be configured to be responsive to a combination of two or morestimuli. For example, the cushioning or bulking materials may beconfigured to be responsive to both temperature and pH level. Such amaterial may be useful for delivery of various forms of drugs because itmay be desirable to be able to control delivery of various drugs (e.g.,by increasing swelling of the material for diffusion-controlled releaseof a drug) without bringing the LCST above, for example, 37° C. Suitablematerials may include, but are not limited to, N-isopropylacrylamide(NIP) polymerized with either Maleic Acid (MAc), which is a diproticacid, or Acrylic Acid (AAc), which is a monoprotic acid.

In an exemplary sample tested, NIP polymerized with MAc (i.e., pNIP MAc)demonstrated greater swelling over NIP polymerized with AAc (i.e., pNIPAAc). The LCST increase for MAc was observed at a pH corresponding todeprotonation of almost all of the first acid groups. Further increasesin pH led to deprotonation of the second —OH and only served to increasethe charge concentration at a given location. These results may providestrong support for the theory that LCST results largely fromuninterrupted chain lengths of NIP and that swelling results from actualcharge density of acid groups along the chain.

In an alternative embodiment, a two-part mixed component that includes,for example, an expandable urethane foam may be used to lift or raisetissue during a medical procedure.

In still other exemplary embodiments, polyvinyl alcohol (PVA), gelatinparticles, collagen, alginates, or any other embolic agents known in theart may be used as a bulking or cushioning material. For example,PVA-based or gelatin-based microspheres (500-900 μm) may be prehydratedin saline for injection into a target site.

Certain injection agents may be formulated as precursors to across-linked agent which may be formed in-situ. For example, calciumions may cross-link alginate, and dialdehyde (e.g., succindlaldehyde,glutaraldehyde, carbodiimide, etc.) may cross-link collagen. If suchprecursors are injected together or mixed just prior to injection, theinjection agent may set up in-situ. By cross-linking the precursors, therelative volumes or concentrations of the precursors may be altered toobtain the desired delivery and/or setup characteristics. In variousalternative or additional embodiments, other suitable cross-linkingagents known in the art may be used. For example, various energy sources(such as heat, radiation, ultrasound, light, etc.) may be used tocross-link the precursors.

In various exemplary embodiments, imaging agents, such as, for example,fluorescent dye, colorants, crystal violet, fillers, or any other agentsknown in the art, may be added to the bulking or cushioning material. Inanother exemplary embodiment, one or more therapeutic agents may beadded so as to be delivered to the body with the material. For example,a cancer-treating agent, such as endostatin, may be added to thematerial. Other agents, such as, for example, hormones,anti-inflammatory agents, antibiotics, pain-relieving agents,antibacterial agents, and/or anti-fungal agents, may additionally oralternatively be added.

With reference to FIGS. 1-6, the methods and systems according tovarious exemplary embodiments of the invention will be described. Asmentioned above, while an embodiment of the invention will be describedin connection with a particular endoscopic procedure in the GI tract,embodiments of the invention may be used with other suitable endoscopicprocedures, or for procedures other than the endoscopic procedures, suchas urologic procedures, plastic surgeries, or open invasive surgeries.In addition, embodiments of the invention may be applied to numerousothers parts of a body, different from the GI tract. In addition, whilethe embodiment of FIGS. 1-6 is described in connection with an LCSTmaterial, the method may be used with materials that transition from afluid to a gel phase due to other stimuli such as a pH change.

FIGS. 1-6 are cross-sectional views of a portion in the GI tract showingthe mucosal and submucosal tissue layers 10, 20, and illustrate a deviceand method for performing a fluid-assisted endoscopic resection ofdiseased tissue 15 in the mucosal tissue layer 10.

As shown in FIG. 2, the device may include an injection needle 50 thatmay be inserted into esophagus by any suitable means, such as through alumen of an endoscope (not shown), so that its distal end portion may bepositioned in the vicinity of a target site. The needle 50 may include ahollow lumen through which the LCST material 55 may flow. The distal endof the needle 50 may include a sharp edge configured to pierce throughtissue layers 10, 20, so that the distal end of the needle 50 may bepositioned between the mucosal tissue layer 10 and the submucosal tissuelayer 20 to deliver the LCST material 55 therein. The amount of LCSTmaterial to be injected may depend on various factors, such as, forexample, type of procedure performed, type of resection instrument used,size of the diseased tissue, or desired degree of bulking or cushioning.

Once the LCST material 55 is injected between the mucosal and submucosaltissue layers 10, 20, due to heat transfer from the body, thetemperature of the LCST material 55 may rise to its LCST and transitionto the gel phase. This may form a stable three-dimensional gel andprovide a stable cushioning against a portion of the mucosal tissuelayer 10 containing the diseased tissue 15, as shown in FIG. 3.

While the LCST material 55 remains in the gel state, a suitableendoscopic resection device 60 having a suitable cutting member 65(e.g., biopsy forceps, snare, scissors, etc.) may be used to remove thediseased tissue 15 from the mucosal tissue layer 10, as shown in FIG. 4.The device 60 may be delivered to the tissue site by any suitable meansknown in the art, such as through a lumen of an endoscope. The LCSTmaterial 55 may maintain its stable three-dimensional shape throughoutthe procedure. The material 55 may stay in place even if the cushionedportion 19 is torn or ruptured due to the tissue-removing procedure, asshown in FIG. 5.

To remove the LCST material 55 after the diseased tissue is fullyremoved or otherwise treated, cold water or saline 75 may be injectedvia a suitable injection needle 70 (which may be the same needle 50 usedto inject the LCST material) into the cushioned portion so that thetemperature of the LCST material 55 may fall below its LCST, as shown inFIG. 5, causing the phase change from the gel phase back to the liquidphase. The LCST material 55 may then be readily washed away from thesite with the injected water or saline 75. Alternatively, if the LCSTmaterial 55 is made of a bioabsorbable material, the material 55 may beleft in place until it naturally dissolves away by itself. FIG. 6 showsthe portion of the mucosal and submucosal tissue layers after theabove-described endoscopic procedure is completed.

While the figures show that the diseased tissue 15 is located in themucosal tissue layer 10, a similar device and method may be used forcases where the diseased tissue 15 is located in the submucosal tissuelayer 20.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

What is claimed is:
 1. A method of injecting fluid into a body, comprising: injecting a material in a liquid phase under a tissue surface, wherein injecting the material causes the tissue surface to protrude into a tract of the body; wherein after the injecting step, the material transitions from the liquid phase to a gel phase in response to a raise in temperature of the material so that the tissue surface remains protruded into the tract; and performing a medical procedure in the tract.
 2. The method of claim 1, wherein the medical procedure is a tissue resection.
 3. The method of claim 1, wherein the medical procedure is a dissection of the submucosal tissue.
 4. The method of claim 1, wherein the material remains in the gel phase for at least approximately 30 minutes.
 5. The method of claim 1, wherein the material transitions from the gel phase into a second liquid phase.
 6. The method of claim 5, further comprising: flushing the material in the second liquid phase.
 7. The method of claim 1, wherein the material is degradable.
 8. The method of claim 1, wherein the material contains a therapeutic agent and is configured to release the therapeutic agent into the body.
 9. The method of claim 1, wherein the stimulus is one of light, pH change, or temperature change.
 10. A method of injecting material into a body, comprising: injecting a material in a liquid phase under a tissue surface defining a tract; wherein after the injecting step, the material transitions from the liquid phase to a gel phase in response to a raise in temperature of the material; and performing a medical procedure in the tract.
 11. The method of claim 10, wherein the medical procedure is a tissue resection.
 12. The method of claim 10, wherein the medical procedure is a dissection of the submucosal tissue.
 13. The method of claim 10, wherein the material remains in the gel phase for at least approximately 30 minutes.
 14. The method of claim 10, wherein the material transitions from the gel phase into a second liquid phase.
 15. The method of claim 14, further comprising: flushing the material in the second liquid phase.
 16. The method of claim 10, wherein the material is degradable.
 17. The method of claim 10, wherein the material contains a therapeutic agent and is configured to release the therapeutic agent into the body.
 18. A method of injecting material into a body, comprising: injecting a material in a first phase under a tissue surface, wherein injecting the material causes the tissue surface to protrude; wherein after the injecting step, the material transitions from the first phase to a second phase in response to a raise in temperature of the material so that the tissue surface remains protruded; and performing a medical procedure on the protruded tissue. 